Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive

ABSTRACT

The present invention relates to β-adrenergic blockers nitrooxyderivatives of general formula (I):
 
A-(Y—ONO 2 ) s  
 
and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine headache and vascular diseases.

The present invention relates to β-adrenergic blockers derivatives. Moreparticularly, the present invention relates to β-adrenergic blockersnitrooxyderivatives, pharmaceutical compositions containing them andtheir use for the treatment of hypertension, cardiovascular diseases,glaucoma, migraine headache, vascular diseases and elevated intraocularpressure.

β-adrenergic blockers (β-blockers) are widely used in the treatment ofhypertension and cardiovascular diseases including angina pectoris,arrhythmias, acute myocardial infarction, hypertrophic cardiomyopathy,congestive heart failure.

They work to block the effects of catecholamines at receptor sites inthe heart, but they differ somewhat in their ability to block receptorsin the blood vessels and lungs. Selective β-blockers have their majoractions on the heart, some others are weak stimulators of the β-receptorwhile still blocking the major actions of catecholamines, some blockboth the β₁ and β₂ receptors in the heart and those in the blood vesselsand have no stimulatory activity and some block other cathecolaminereceptors that can lead to further vascular effects on blood vessels.

Several side effects are associated with this class of drugs such asmuscle fatigue, sleep disturbances, decreased heart rate, hypotension,cold extremities, bronchospasm in asthmatic patients, hypoglycemia,increased in plasma lipids.

Moreover, abrupt withdrawal after long-term treatment with β-blockershas to be avoided, because an increased sensitivity to β-adrenergicsystem develops

U.S. Pat. No. 6,242,432 discloses derivatives of formula A-(X₁—NO₂)_(to)having an antithrombotic activity, wherein A is the residue of aβ-adrenergic blocker, X₁ is a bivalent connecting bridge and t_(o) is 1or 2. The invention is limited to particular residues of β-adrenergicblockers.

U.S. Pat. No. 5,502,237 and U.S. Pat. No. 5,639,904 disclose derivativesof formula R₁—Ar—O—CH₂—CH(OH)—CH₂—NH—CH(CH₃)₂ used for the treatment ofcardiovascular affections, wherein R₁ is a chain having at least onenitrooxy group as substituent.

U.S. Pat. No. 4,801,596 discloses aminopropanol derivatives of formula

that can be used for prophylaxis and/or treatment of heart andcirculatory diseases, wherein R₃ is an alkyl or a nitrooxyalkyl radicalcontaining 3 to 8 carbon atoms.

It was an object of the present invention to provide new β-adrenergicblockers nitrooxyderivatives having a significantly improved overallpharmacological profile as compared to native β-blockers that are ablenot only to eliminate or at least reduce the side effects associatedwith their parent compounds, but also having an improved pharmacologicalactivity and tolerability.

It has been so surprisingly found that the β-adrenergic blockersnitrooxyderivatives of the present invention have a betterpharmacological activity and organ protection properties, enhancedeffects as anti-inflammatory, and on renal functions. In addition, theyare effective in other pathologies including atherosclerosis, diabetes,peripheral vascular diseases (PVD) and elevated intraocular pressure.

In particular, it has been recognized that the β-adrenergic blockersnitrooxyderivatives of the present invention, differently from the abovementioned compounds of the prior art, exhibit an improved activity onthe cardiovascular system and enhanced tolerability and can be employedfor treating or preventing hypertension, cardiovascular diseases,glaucoma, migraine headache, vascular diseases and elevated intraocularpressure.

Object of the present invention are β-adrenergic blockersnitrooxyderivatives of general formula (I):A-(Y—ONO₂)_(s)

and enantiomers and diastereoisomers and pharmaceutically acceptablesalts thereof,

wherein s is an integer equal to 1 or 2;

A is selected from the following β-adrenergic blocker residues offormula (II):

wherein

R₁ is selected from the group consisting of:

R₂ is selected from the group consisting of: —CH(CH₃)₂, —C(CH₃)₃ or

when the radical R₁ has chosen from the formulae (IIa), (IIc), (IId),(IIg), (IIh), (IIi), (IIm), R₂ is —CH(CH₃)₂;

when the radical R₁ has chosen from the formulae (IIe), (IIf) or (IIn),R₂ is —C(CH₃)₃;

when R₁ is the radical (IIb), R₂ is (IIIa);

when R₁ is the radical (IIL), R₂ is (IIIb);

Z is H or is a group capable of binding Y selected from the groupconsisting of:

wherein R′ and R″ are the same or different, and are H or straight orbranched C₁-C₄ alkyl;

Z₁ is H or a —C(O)— capable of binding Y;

with the proviso that when s of formula (I) is 1, Z or Z₁ is H;

preferably when s of formula (I) is 2, Z and Z₁ are —C(O)—;

Y is a bivalent radical having the following meanings:

a)

straight or branched C₁-C₂₀ alkylene, preferably C₁-C₁₀ alkylene, morepreferably C₃-C₆ alkylene, being optionally substituted with one or moreof the substituents selected from the group consisting of: halogenatoms, hydroxy, —ONO₂ or T, wherein T is —OC(O)(C₁-C₁₀alkyl)-ONO₂,—O(C₁-C₁₀alkyl)-ONO₂;

b)

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ringbeing optionally substituted with side chains T₁, wherein T₁ is straightor branched alkyl with from 1 to 10 carbon atoms, T₁ is preferably CH₃;

c)

wherein:

n is an integer from 0 to 20, preferably n is an integer from 0 to 10,more preferably n is 0 or 1,

n1 is an integer from 1 to 20, preferably from 1 to 10, more preferablyn1 is 1;

n2, n3, n4 and n5 are integers equal or different from one another,equal to 0 or 1;

R³ and R⁴ are independently selected from H or CH₃;

Y¹ is —CH₂— or —(CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20,preferably na is equal to 0;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is oxygen;

d)

wherein:

n1 is an integer from 1 to 20, preferably from 1 to 10;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is sulfur or NH,

n6 is an integer from 1 to 20, preferably from 1 to 5, more preferablyn6 is 1,

n7 is an integer from 0 to 20, preferably from 0 to 5, more preferablyn7 is 1,

R⁵, R^(5′), R⁶ and R^(6′) are independently selected from the groupconsisting of: H, CH₃, OH, NH₂, NHCOCH₃, COOH, CH₂SH and C(CH₃)₂SH;

when the bond between the C^(A) and C^(B) carbons is a double bond R⁵and R⁶ or R^(6′) and R^(5′) are absent;

with the proviso that when Y is selected from the bivalent radicalsmentioned under c)-d), the —ONO₂ group is linked to the —(CH₂)_(n1)—group;

e)

wherein X₂ is O or S,

n10a, n10 and n12 are integer independently selected from 0 to 20,

n10a is preferably selected from 0 to 10, more preferably n10a is 0 or1,

n10 and n12 are preferably selected from 1 to 10, more preferably n10and n12 are 1 or 2

n11 is an integer from 0 to 6, preferably from 0 to 4, more preferablyn11 is 0 or 1,

R¹¹ is H, CH₃ or nitrooxy group, preferably R¹¹ is H or a nitrooxy groupand

R^(11a) is CH₃ or nitrooxy group;

f)

wherein

n8 is an integer from 0 to 10;

n9 is an integer from 1 to 10;

R⁹, R¹⁰, R⁸, R⁷ are same or different, and are H or straight or branchedC₁-C₄ alkyl, preferably R⁹, R¹⁰, R⁸, R⁷ are H;

wherein the —ONO₂ group is linked to

wherein n9 is as defined above;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulfur,

and is selected from the group consisting of

One embodiment provides compounds of formula (I) wherein:

s is 2,

A is selected from the following β-adrenergic blocker residues offormula (II):

wherein

R₁ is selected from the group consisting of:

R₂ is selected from the group consisting of: —CH(CH₃)₂, —C(CH₃)₃ or

when the radical R₁ has chosen from the formulae (IIa), (IIc), (IId),(IIg), (IIh), (IIi), (IIm), R₂ is —CH(CH₃)₂;

when the radical R₁ has chosen from the formulae (IIe), (IIf) or (IIn),R₂ is —C(CH₃)₃;

when R₁ is the radical (IIb), R₂ is (IIIa);

when R₁ is the radical (IIL), R₂ is (IIIb);

Z is a group capable of binding Y selected from the group consisting of:

—C(O)—, —C(O)O— or

wherein R′ and R″ are the same or different, and are H or straight orbranched C₁-C₄ alkyl;

Z₁ is H or a —C(O)— capable of binding Y, preferably Z and Z₁ are—C(O)—;

Y is a bivalent radical having the following meaning:

a)

straight or branched C₁-C₂₀ alkylene, preferably C₁-C₁₀ alkylene, morepreferably C₃-C₆ alkylene, being optionally substituted with one or moreof the substituents selected from the group consisting of: halogenatoms, hydroxy, —ONO₂ or T, wherein T is —OC(O)(C₁-C₁₀alkyl)-ONO₂,—O(C₁-C₁₀alkyl)-ONO₂;

b)

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ringbeing optionally substituted with side chains T₁, wherein T₁ is straightor branched alkyl with from 1 to 10 carbon atoms, T₁ is preferably CH₃;

c)

wherein:

n is an integer from 0 to 20, preferably n is an integer from 0 to 10,more preferably n is 0 or 1,

n1 is an integer from 1 to 20, preferably from 1 to 10, more preferablyn1 is 1;

n2, n3, n4 and n5 are integers equal or different from one another,equal to 0 or 1;

R³ and R⁴ are independently selected from H or CH₃;

Y¹ is —CH₂— or —(CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20,preferably na is equal to 0;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is oxygen;

d)

wherein:

n1 is an integer from 1 to 20, preferably from 1 to 10;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is sulfur or NH;

n6 is an integer from 1 to 20, preferably from 1 to 5, more preferablyn6 is 1,

n7 is an integer from 0 to 20, preferably from 0 to 5, more preferablyn7 is 1,

R⁵ and R^(5′) R⁶ and R^(6′) are independently selected from the groupconsisting of: H, CH₃, OH, NH₂, NHCOCH₃, COOH, CH₂SH and C(CH₃)₂SH;

when the bond between the C^(A) and C^(B) carbons is a double bond R⁵and R⁶ or R^(6′) and R^(5′) are absent;

with the proviso that when Y is selected from the bivalent radicalsmentioned under c)-d), the —ONO₂ group is linked to the —(CH₂)_(n1)—group;

e)

wherein X₂ is O or S,

n10a, n10 and n12 are integer independently selected from 0 to 20,

n10a is preferably selected from 0 to 10, more preferably n10a is 0 or1;

n10 and n12 are preferably selected from 1 to 10, more preferably n10and n12 are 1 or 2;

n11 is an integer from 0 to 6, preferably from 0 to 4, more preferablyn11 is 0 or 1;

R¹¹ is H, CH₃ or nitrooxy group, preferably R¹¹ is H or nitroxy;

R^(11a) is CH₃ or nitrooxy group;

f)

wherein

n8 is an integer from 0 to 10;

n9 is an integer from 1 to 10;

R⁹, R¹⁰, R⁸, R⁷ are same or different, and are H or straight or branchedC₁-C₄ alkyl, preferably R⁹, R¹⁰, R⁸, R⁷ are H;

wherein the —ONO₂ group is linked to

wherein n9 is as defined above;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulfur,

and is selected from the group consisting of

Another embodiment provides compounds of formula (I) wherein:

s is 1,

A is selected from the following β-adrenergic blocker residues offormula (II):

wherein

R₁ is selected from the group consisting of:

R₂ is selected from the group consisting of: —CH(CH₃)₂, —C(CH₃)₃ or

when the radical R₁ has chosen from the formulae (IIa), (IIc), (IId),(IIg), (IIh), (IIi), (IIm), R₂ is —CH(CH₃)₂;

when the radical R₁ has chosen from the formulae (IIe), (IIf) or (IIn),R₂ is —C(CH₃)₃;

when R₁ is the radical (IIb), R₂ is (IIIa);

when R₁ is the radical (IIL), R₂ is (IIIb);

Z is H and Z₁ a —C(O)— capable of binding Y;

Y is a bivalent radical having the following meaning:

a)

straight or branched C₁-C₂₀ alkylene, preferably C₁-C₁₀ alkylene, morepreferably C₃-C₆ alkylene, being optionally substituted with one or moreof the substituents selected from the group consisting of: halogenatoms, hydroxy, —ONO₂ or T, wherein T is —OC(O)(C₁-C₁₀alkyl)-ONO₂,—O(C₁-C₁₀alkyl)-ONO₂;

b)

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ringbeing optionally substituted with side chains T₁, wherein T₁ is straightor branched alkyl with from 1 to 10 carbon atoms, T₁ is preferably CH₃;

c)

wherein:

n is an integer from 0 to 20, preferably n is an integer from 0 to 10,more preferably n is 0 or 1, and n1 is an integer from 1 to 20,preferably from 1 to 10, more preferably n1 is 1;

n2, n3, n4 and n5 are integers equal or different from one another,equal to 0 or 1;

R³ and R⁴ are independently selected from H or CH₃;

Y¹ is —CH₂— or —(CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20,preferably na is equal to 0;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is oxygen;

d)

wherein:

n1 is an integer from 1 to 20, preferably from 1 to 10;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is sulfur or NH;

n6 is an integer from 1 to 20, preferably from 1 to 5, more preferablyn6 is 1,

n7 is an integer from 0 to 20, preferably from 0 to 5, more preferablyn7 is 1,

R⁵ and R^(5′) R⁶ and R^(6′) are independently selected from the groupconsisting of: H, CH₃, OH, NH₂, NHCOCH₃, COOH, CH₂SH and C(CH₃)₂SH;

when the bond between the C^(A) and C^(B) carbons is a double bond R⁵and R⁶ or R^(6′) and R^(5′) are absent;

with the proviso that when Y is selected from the bivalent radicalsmentioned under c)-d), the —ONO₂ group is linked to a —(CH₂)_(n1)—group;

e)

wherein X₂ is O or S,

n10a, n10 and n12 are integer independently selected from 0 to 20,

n10a is preferably selected from 0 to 10, more preferably n10a is 0 or1;

n10 and n12 are preferably selected from 1 to 10, more preferably n10and n12 are 1 or 2;

n11 is an integer from 0 to 6, preferably from 0 to 4, more preferablyn11 is 0 or 1;

R¹¹ is H, CH₃ or nitrooxy group, preferably R¹¹ is H or nitroxy;

R^(11a) is CH₃ or nitrooxy group;

f)

wherein

n8 is an integer from 0 to 10;

n9 is an integer from 1 to 10;

R⁹, R¹⁰, R⁸, R⁷ are same or different, and are H or straight or branchedC₁-C₄ alkyl, preferably R⁹, R¹⁰, R⁸, R⁷ are H;

wherein the —ONO₂ group is linked to

wherein n9 is as defined above;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulfur,

and is selected from the group consisting of

Another embodiment provides compounds of formula (I) wherein

s is 1,

A is selected from the following β-adrenergic blocker residues offormula (II):

wherein

R₁ is selected from the group consisting of:

R₂ is selected from the group consisting of: —CH(CH₃)₂, —C(CH₃)₃ or

when the radical R₁ has chosen from the formulae (IIa), (IIc), (IId),(IIg), (IIh), (IIi), (IIm), R₂ is —CH(CH₃)₂;

when the radical R₁ has chosen from the formulae (IIe), (IIf) or (IIn),R₂ is —C(CH₃)₃;

when R₁ is the radical (IIL), R₂ is (IIIb);

Z₁ is H;

Z is a group capable of binding Y selected from the group consisting of:

—C(O)—, —C(O)O— or

wherein R′ and R″ are the same or different, and are H or straight orbranched C₁-C₄ alkyl;

Y is a bivalent radical having the following meaning:

c)

wherein:

n is an integer from 0 to 20, preferably n is an integer from 0 to 10,more preferably n is 0 or 1,

n1 is an integer from 1 to 20, preferably from 1 to 10, more preferablyn1 is 1;

n2, n3, n4 and n5 are integers equal or different from one another,equal to 0 or 1;

R³ and R⁴ are independently selected from H or CH₃;

Y¹ is —CH₂— or —(CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20,preferably na is equal to 0;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is oxygen;

e)

wherein

X₂ is O or S,

n10a is 0 or 1,

n11 is 0 or 1,

n10 and n12 are or 2;

R¹¹ is H, CH₃ or nitrooxy group;

R^(11a) is CH₃ or nitrooxy group;

f)

wherein

n8 is an integer from 0 to 10;

n9 is an integer from 1 to 10;

R⁹, R¹⁰, R⁸, R⁷ are same or different, and are H or straight or branchedC₁-C₄ alkyl, preferably R⁹, R¹⁰, R⁸, R⁷ are H;

wherein the —ONO₂ group is linked to

wherein n9 is as defined above;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulfur,

and is selected from the group consisting of

Another embodiment provides compounds of formula (I) wherein

s is an integer equal to 1 or 2

A is the β-adrenergic blocker residue of formula (II):

wherein

R₁ is (IIb)

R₂ is (IIa)

Z is H or is a group capable of binding Y selected from the groupconsisting of:

wherein R′ and R″ are the same or different, and are H or straight orbranched C₁-C₄ alkyl;

Z₁ is H or a —C(O)— capable of binding Y;

with the proviso that when s of formula (I) is 1, Z or Z₁ is H;

preferably when s of formula (I) is 2, Z and Z₁ are —C(O)—;

Y is a bivalent radical having the following meaning:

a)

straight or branched C₁-C₂₀ alkylene, preferably; C₁-C₁₀ alkylene, morepreferably C₃-C₆ alkylene, being optionally substituted with one or moreof the substituents selected from the group consisting of: halogenatoms, hydroxy, —ONO₂ or T, wherein T is —OC(O)(C₁-C₁₀alkyl)-ONO₂,—O(C₁-C₁₀alkyl)-ONO₂;

b)

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ringbeing optionally substituted with side chains T₁, wherein T₁ is straightor branched alkyl with from 1 to 10 carbon atoms, T₁ is preferably CH₃;

c)

wherein:

n is an integer from 0 to 20, preferably n is an integer from 0 to 10,more preferably n is 0 or 1,

n1 is an integer from 1 to 20, preferably from 1 to 10, more preferablyn1 is 1,

n2, n3, n4 and n5 are integers equal or different from one another,equal to 0 or 1,

R³ and R⁴ are independently selected from H or CH₃;

Y¹ is —CH₂— or —(CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20,preferably na is equal to 0;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is oxygen;

d)

wherein:

n1 is an integer from 1 to 20, preferably from 1 to 10;

X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferablyW is sulfur or NH;

n6 is an integer from 1 to 20, preferably from 1 to 5, more preferablyn6 is 1,

n7 is an integer from 0 to 20, preferably from 0 to 5, more-preferablyn7 is 1,

R⁵ and R^(5′) R⁶ and R⁶ are independently selected from the groupconsisting of: H, CH₃, OH, NH₂, NHCOCH₃, COOH, CH₂SH and C(CH₃)₂SH;

when the bond between the C^(A) and C^(B) carbons is a double bond R⁵and R⁶ or R^(6′) and R^(5′) are absent;

with the proviso that when Y is selected from the bivalent radicalsmentioned under c)-d), the —ONO₂ group is linked to a —(CH₂)_(n1)—group;

e)

wherein X₂ is O or S, n10a, n10 and n12 are integer independentlyselected from 0 to 20,

n10a is preferably selected from 0 to 10, more preferably n10a is 0 or1;

n10 and n12 are preferably selected from 1 to 10, more preferably n10and n12 are 1 or 2,

n11 is an integer from 0 to 6, preferably from 0 to 4, more preferablyn11 is 0 or 1;

R¹¹ is H, CH₃ or nitrooxy group, preferably R¹¹ is H or a nitrooxygroup,

R^(11a) is CH₃ or nitrooxy group;

f)

wherein

n8 is an integer from 0 to 10;

n9 is an integer from 1 to 10;

R⁹, R¹⁰, R⁸, R⁷ are same or different, and are H or straight or branchedC₁-C₄ alkyl, preferably R⁹, R¹⁰, R⁸, R⁷ are H;

wherein the —ONO₂ group is linked to

wherein n9 is as defined above;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulfur,

and is selected from the group consisting of

Preferred compounds are those of formula (I) wherein:

s is 2,

A is a β-adrenergic blocker residues of formula (II) as above defined

Z and Z₁ are —(CO)—

Y is a bivalent radical having the following meanings:

a) straight C₁-C₁₀ alkylene, preferably C₃-C₆ alkylene;

c)

wherein the —ONO₂ group is bound to (CH₂)_(n1);

n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the —(CH₂)_(n1)— group isbound to the phenyl ring through the [C]₂ or [C]₃ or [C]₄;

or n, n2, n5 are 1, n3 and n4 are equal to 0, and

n1 is an integer from 1 to 10,

Y¹ is —(CH₂)_(na)—CH═CH— wherein na is 0, X₁ is —WC(O)— wherein W isoxygen and the WC(O) group is bound to the phenyl ring through the [C]₄,R⁴ is CH₃ and the (OR⁴) group is bound to the phenyl ring through the[C]₃;

d)

wherein

n1 is an integer from 1 to 10,

n6 and n7 are 1,

X₁ is —WC(O)— wherein W is sulfur,

R⁵, R^(5′) and R^(6′) are H, R⁶ is NHCOCH₃ and

the —ONO₂ is bound to the —(CH₂)_(n1)— group;

e)

wherein

X₂ is O or S, and n11 is 0,

n10a is an integer from 0 to 10,

n12 is an integer from 1 to 10,

R¹¹ is H or a nitrooxy group

and the —ONO₂ group is bound to (CH₂)_(n12);

Another group of preferred compounds comprises compounds of formula (I)

wherein

s is 1,

A is a β-adrenergic blocker residues of formula (II) as above defined,

Z is H,

Z₁ is —(CO)—

Y is a bivalent radical having the following meanings:

a) straight C₁-C₁₀ alkylene, preferably C₃-C₆ alkylene;

c)

wherein the —ONO₂ group is bound to (CH₂)_(n1);

n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the —(CH₂)_(n1)— group isbound to the phenyl ring through the [C]₂ or [C]₃ or [C]₄;

or n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer from1 to 10, Y¹ is —(CH₂)_(na)—CH═CH— wherein na is 0, X₁ is —WC(O)— whereinW is oxygen and the WC(O) group is bound to the phenyl ring through the[C]₄, R⁴ is CH₃ and the (OR⁴) group is bound to the phenyl ring throughthe [C]₃;

d)

wherein

n1 is an integer from 1 to 10;

X₁ is —WC(O)— wherein W is sulfur;

n6 is 1

n7 is 1,

R⁵, R^(5′) and R^(6′) are H, R⁶ is, NHCOCH₃ and

the —ONO₂ is bound to the —(CH₂)_(n1)— group;

e)

wherein

X₂ is O or S, and n11 is 0,

n10a is an integer from 0 to 10,

n12 is an integer from 1 to 10,

R¹¹ is H or a nitrooxy group

and the —ONO₂ group is bound to (CH₂)_(n12);

Another group of preferred compounds comprises compounds of formula (I)

wherein

s is 1,

A is a β-adrenergic blocker residues of formula (II) as above defined,

Z₁ is H,

Z is —(CO)— or —C(O)O— and

Y is a bivalent radical having the following meanings:

c)

wherein the —ONO₂ group is bound to (CH₂)_(n1);

n, n2, n3, n4, n5 are equal to 0,

n1 is 1 and the —(CH₂)_(n1)— group is bound to the phenyl ring throughthe [C]₂ or [C]₃ or [C]₄;

or in formula (IV)

n, n2, n5 are 1,

n3 and n4 are equal to 0,

n1 is an integer from 1 to 10,

Y¹ is —(CH₂)_(na)—CH═CH— wherein na is 0, X₁ is —WC(O)— wherein W isoxygen and the WC(O) group is bound to the phenyl ring through the [C]₄,R⁴ is CH₃ and the (OR⁴) group is bound to the phenyl ring through the[C]₃;

Another groups of preferred compounds comprises compounds of formula (I)wherein:

s is 1,

A is the β-adrenergic blocker residues of formula (II) wherein

R₁ is

R₂ is

Z₁ is H and Z is —(CO)— or —C(O)O— and

Y is a bivalent radical having the following meanings:

a) straight C₁-C₁₀ alkylene, preferably C₃-C₆ alkylene;

c)

wherein the —ONO₂ group is bound to (CH₂)_(n1);

n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the —(CH₂)_(n1)— group isbound to the phenyl ring through the [C]₂ or [C]₃ or [C]₄;

or in formula (IV)

n, n2, n5 are 1, n3 and n4 are equal to 0,

n1 is an integer from 1 to 10,

Y¹ is —(CH₂)_(na)—CH═CH— wherein na is 0,

X₁ is —WC(O)— wherein W is oxygen and the WC(O) group is bound to thephenyl ring through the [C]₄, R⁴ is CH₃ and the (OR⁴) group is bound tothe phenyl ring through the [C]₃;

d)

wherein

n1 is an integer from 1 to 10,

n6 and n7 are 1,

X₁ is —WC(O)— wherein W is sulfur,

R⁵, R^(5′) and R^(6′) are H, R⁶ is NHCOCH₃ and

the —ONO₂ is bound to the —(CH₂)_(n1)— group;

e)

wherein

X₂ is O or S, and n11 is 0,

n10a is an integer from 0 to 10,

n12 is an integer from 1 to 10,

R¹¹ is H or a nitrooxy group

and the —ONO₂ group is bound to (CH₂)_(n12).

Most preferred compounds of formula (I) according to the presentinvention are the following:

Examples of “straight or branched C₁-C₂₀ alkylene” include, but are notlimited to, methylene, ethylene, propylene, isopropylene, n-butylene,pentylene, n-hexylene and the like.

As stated above, the invention includes also the pharmaceuticallyacceptable salts of the compounds of formula (I) and stereoisomersthereof.

Examples of pharmaceutically acceptable salts are either those withinorganic bases, such as sodium, potassium, calcium and aluminiumhydroxides, or with organic bases, such as lysine, arginine,triethylamine, dibenzylamine, piperidine and other acceptable organicamines.

The compounds according to the present invention, when they contain inthe molecule one salifiable nitrogen atom, can be transformed into thecorresponding salts by reaction in an organic solvent such asacetonitrile, tetrahydrofuran with the corresponding organic orinorganic acids.

Examples of pharmaceutical acceptable organic acids are: oxalic,tartaric, maleic, succinic, citric acids. Examples of pharmaceuticalacceptable inorganic acids are: nitric, hydrochloric, sulphuric,phosphoric acids. Salts with nitric acid are preferred.

The compounds of the invention which have one or more asymmetric carbonatoms can exist as optically pure enantiomers, pure diastereomers,enantiomers mixtures, diastereomers mixtures, enantiomer racemicmixtures, racemates or racemate mixtures. Within the object of theinvention are also all the possible isomers, stereoisomers and theirmixtures of the compounds of formula (I).

The compounds and compositions of the present invention can beadministered by any available and effective delivery system includingbut not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles. Parenteral includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion technique.

Solid dosage forms for oral administration can include for examplecapsule, tablets, pills, powders, granules and gel. In such solid dosageforms, the active compounds can be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage form can alsocomprise, as normal practice, additional substance other than inertdiluent, e.g., lubricating agent such as magnesium stearate.

Injectable preparations, for example sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents.

The composition of this invention can further include conventionalexcipients, i.e., pharmaceutical acceptable organic or inorganicsubstances which do not deleteriously react with the active compounds.

The doses of β-adrenergic blockers nitrooxyderivatives can bedeterminated by standard clinique technique and are in the same rangesor less than as described for commercially available compounds asreported in the: Physician's Desk Reference, Medical Economics Company,Inc., Oradell, N. J., 58^(th) Ed., 2004; The pharmacological basis oftherapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20^(th)Ed.

EXPERIMENTAL Synthesis Procedure

Compounds of the invention can be synthesized as shown in Schemes 1 to6. Compounds of general formula (I) A-(Y—ONO₂)_(s), defined in Scheme1-3 as compounds of formula D, wherein s is 1, Y is as above defined andA is a 0-adrenergic blocker residue of formula (II), wherein Z is —C(O)—and Z₁ is H, the enantiomers, diastereoisomer and a pharmaceuticallyacceptable salt thereof, can be prepared as outlined in Schemes 1-3.

Compounds of formula (i) wherein R₁, R₂, Z and Y are as above defined,P₁ is an amine protecting group such as tert-butyloxycarbonyl ester(t-Boc) and X₃ is an halogen atom preferably Cl, Br and I, are convertedto compounds of formula (L) wherein R₁, R₂, P₁, Z and Y are as abovedefined, by reaction with AgNO₃ in a suitable organic solvent such asacetonitrile, tetrahydrofurane, a silver nitrate molar excess ispreferably used and the reaction is carried out, in the dark, at atemperature from room temperature to the boiling temperature of thesolvent. The compounds of formula (L) are converted to the compounds offormula (D) by deprotecting the amine group (strong acid, such as HCl indioxane or trifluoroacetic acid, is used to remove a t-butyl carbamate).Other preferred methods for removing the amine protecting groups arethose described in T. W. Greene “Protective groups in organicsynthesis”, Harvard University Press, 1980.

The compounds of formula (H) wherein R₁, R₂, Z, P₁ and Y are as abovedefined, are converted to the esters of formula (i) wherein R₁, R₂, Y,Z, X₃ and P₁ are as above defined, by reaction with an appropriate acid(Q1) of formula X₃—Y—COOH wherein Y and X₃ are as above defined. Thereaction is generally carried out in an inert organic solvent such asN,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, apolyhalogenated aliphatic hydrocarbon at a temperature from 0° C. to 50°C. in presence of a dehydrating agent such as dycyclohexylcarbodiimideDCC or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDAC HCl) with a catalyst, such as 4-N,N-dimethylaminopyridine (DMAP).

The compounds of formula (H) wherein R₁, R₂ and P₁ are as above defined,can be obtained by deprotecting the hydroxylic group of the compounds offormula (G) wherein R₁, R₂ are as above defined and P is a hydroxylicprotecting group such as silyl ethers, such as trimethylsilyl ortert-butyl-dimethylsilyl and those described in T. W. Greene “Protectivegroups in organic synthesis”, Harvard University Press, 1980. Fluorideion is the preferred method for removing silyl ether protecting group.

The compounds of formula (G) wherein R₁, R₂, P and P₁ are as abovedefined, can be obtained by reacting the compounds of formula (F)wherein R₁, R₂ and P are as above defined with a suitable amineprotecting group (P₁) as above described.

The alcohol group of the compounds of formula (A) wherein R₁, R₂ are asabove defined, is protected to afford the compounds of formula (F)wherein R₁, R₂ are as above defined Preferred protecting group for thealcohol moiety are silyl ethers, such as trimethylsilyl ortert-butyl-dimethylsilyl.

The compounds (A) wherein R₁, R₂ are as above defined are commerciallyavailable, the acids of formula X₃—Y—COOH wherein X₃ is as abovedefined, are commercially available.

Compounds of formula (B) wherein R₁, R₂, Z, Y are as above defined andX₃ is an halogen atom, such as Cl, Br and 1, are converted to compoundsof formula (D) wherein R₁, R₂, Z and Y are as above defined, by reactionwith AgNO₃ in a suitable organic solvent such as acetonitrile,tetrahydrofurane, a silver nitrate molar excess is preferably used andthe reaction is carried out, in the dark, at a temperature from roomtemperature and the boiling temperature of the solvent.

The compounds of formula (B) wherein R₁, R₂, Z, Y and X₃ are as abovedefined can be obtained by reaction of the compounds of formula (A) withan appropriate acyl chloride (Q) of formula X₃—Y—C(O)Cl, wherein X₃ ischosen among chlorine, bromine, and Y is as above defined. Theesterification is carried out in an inert organic solvent such asN,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform inpresence of a base as triethylamine, pyridine at a temperature from roomtemperature and 50° C. The reaction is completed within a time rangefrom 30 minutes to 24 hours.

Alternatively the compounds of formula (B) can be obtained by reactionof compounds of formula (A) with an acid (Q1) of formula X₃—Y—C(O)OH inthe presence of a dehydrating agent as dicyclohexylcarbodiimide (DCC) orN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) anda catalyst, such as N,N-dimethylamino pyridine. The reaction is carriedout in an inert organic solvent such as as N,N′-dimethylformamide,tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatichydrocarbon at a temperature from 0° C. and 50° C. The reaction iscompleted within a time range from 30 minutes to 36 hours.

The compounds of formula (Q1), where X₃ is an halogen atom arecommercially available or can be obtained from the correspondingcommercially available hydroxy acid by well known reactions, for exampleby reaction with thionyl or oxalyl chloride, halides of P^(III) or P^(V)in solvents inert such as toluene, chloroform, DMF, etc.

The compounds (A) wherein R₁, R₂ are as above defined are commerciallyavailable

Alternatively the compounds of formula (D) can be obtained as describedbelow. The compounds of formula are converted to the compounds (D) byreaction of hydroxy group with a nitrooxy derivative, containingactivated acylating group, of formula Cl(O)C—Y—ONO₂.

The nitrooxy compounds can be obtained from the corresponding alcoholsof formula Cl(O)C—Y—OH by reaction with nitric acid and acetic anhydridein a temperature range from −50° C. to 0° C. or from the correspondinghalogen derivatives of formula Cl(O)C—Y-Hal by reaction with silvernitrate in the presence of an inert solvent such as acetonitrile,tetrahydrofurane. A silver nitrate molar excess is preferably used andthe reaction is carried out, in the dark, a temperature from the boilingtemperature and room temperature. The reaction is completed within atime range from 30 minutes to 3 days.

The compounds of general formula (I) A-(Y—ONO₂)_(s), defined in Scheme 4as compounds of formula (D1), wherein s is 1, Y is as above defined andA is a β-adrenergic blocker residue of formula (II), wherein Z is—C(O)O— and Z₁ is H, the enantiomers, diastereoisomer and apharmaceutically acceptable salt thereof, can be prepared as outlined inScheme 4.

The compounds of formula (B1) wherein R₁, R₂, Y are as above defined andX₃ is an halogen atom, such as Cl, Br and I, are converted to compoundsof formula (D1) wherein R₁, R₂, and Y are as above defined, by reactionwith AgNO₃ in a suitable organic solvent such as acetonitrile,tetrahydrofurane, a silver nitrate molar excess is preferably used andthe reaction is carried out, in the dark, at a temperature from roomtemperature and the boiling temperature of the solvent.

The compounds of formula (A) wherein R₁ and R₂ are as above defined areconverted to the compounds (B1) by reaction with an appropriate compound(Q2) having formula X₃—Y—OC(O)Cl wherein X₃ is Cl, Br or I, and Y is asdefined above. The reaction is generally carried out in presence of abase in an aprotic polar or non-polar solvent such as THF or CH₂Cl₂ attemperature range between 0°-65° C. or in a double phase system H₂O/Et₂Oat temperature range between 20°-40° C.

The compounds of formula (Q2) are commercially available or can beobtained from the corresponding alcohols by reaction with triphosgene inpresence of an organic base.

The compounds of general formula (I) A-(Y—ONO₂)_(s), defined in Scheme 5as compounds of formula (D), wherein s is 1, Y is as above defined and Ais a β-adrenergic blocker residue of formula (II), wherein Z is

wherein R′ and R″ are H or straight or branched C₁-C₄ alkyl and Z₁ is H,the enantiomers, diastereoisomer and a pharmaceutically acceptable saltsthereof, may be prepared as outlined in Scheme 5:

The compounds of formula (i) wherein R₁, R₂, Z and Y are as abovedefined, P₁ is an amine protecting group such as tert-butyloxycarbonylester (t-Boc) and X₃ is an halogen atom such as Cl, Br and I, areconverted to compounds of formula (L) wherein R₁, R₂, P₁, Z and Y are asabove defined, by reaction with AgNO₃ in a suitable organic solvent suchas acetonitrile, tetrahydrofurane, a silver nitrate molar excess ispreferably used and the reaction is carried out, in the dark, at atemperature from room temperature and the boiling temperature of thesolvent. The compounds of formula (L) are converted to the compounds offormula (D) by deprotecting the amine group (strong acid, such as HCl indioxane or trifluoroacetic acid, is used to remove a t-butyl carbamate).Other preferred methods for removing the amine protecting groups arethose described in T. W. Greene “Protective groups in organicsynthesis”, Harvard University Press, 1980.

The compounds of formula (i) wherein R₁, R₂, Y, X₃, Z and P₁ are asabove defined, can be obtained by reacting the compounds of formula (M)wherein R₁, R₂, P₁, R′, R″ and X₃ are as above defined, with an acid(Q1) of formula X₃—Y—COOH wherein X₃ is an halogen atom and Y is asabove defined. The reaction is carried out in an inert organic solventsuch as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene,dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature rangefrom 0° C. and 50° C. in the presence of a dehydrating agent such asdycyclohexylcarbodiimide DCC or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC HCl)with a catalyst, such as 4-N,N-dimethylaminopyridine (DMAP).

The reaction is complete within a time ranges from 30 minutes to 24hours.

The compounds of formula (M) wherein R₁, R₂, P₁, R′, R″ and X₃ are asabove defined, can be obtained by reacting the compounds the of formula(H) with a compound (S) of formula X₃—C(R′)(R″)—OC(O)X₃ wherein X₃ is anhalogen atom. The reaction is carried out in presence of an organic orinorganic base in a polar solvent as DMF, THF, acetonitrile at atemperature in the range from −5° C. to 60° C. or in a double phasesystem according to methods well known in the literature.

The amine group of the compounds (A) is protected to afford thecompounds of formula (H) wherein P₁ is a suitable amine protecting groupsuch as tert-butyloxycarbonyl ester (t-Boc) The compounds (S) arecommercially available.

The compounds of general formula (I) A-(Y—ONO₂)_(s), defined in Scheme 6as compounds of formula (E), wherein s is 2, Y is as above defined and Ais a β-adrenergic blocker residue of formula (II), wherein Z₁ and Z are—C(O)—, the enantiomers, diastereoisomer and a pharmaceuticallyacceptable salt thereof, can be synthesized as shown in Scheme 6.

Compounds of formula (C) wherein R₁, R₂, Z, Z₁ and Y are as abovedefined and X₃ is an halogen atom, such as Cl, Br and I, are convertedto compounds of formula (E) wherein R₁, R₂, Z and Y are as abovedefined, by reaction with AgNO₃ in a suitable organic solvent such asacetonitrile, tetrahydrofurane, a silver nitrate molar excess ispreferably used and the reaction is carried out, in the dark, at atemperature from room temperature and the boiling temperature of thesolvent.

The compounds of formula (C) wherein R₁, R₂, Z, Z₁, Y and X₃ are asabove defined can be obtained by reaction of the compounds of formula(A) with an appropriate acyl halide (Q) of formula X₃—Y—C(O)Cl, whereinX₃ is chosen among chlorine, bromine, and Y is as above defined. Thereaction is carried out in an inert organic solvent such asN,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform inpresence of a base as triethylamine, pyridine at a temperature from roomtemperature and 50° C. The reaction is completed within a time rangefrom 30 minutes to 24 hours.

Alternatively the compounds of formula (C) can be obtained by reactionof the compounds of formula (A) with an acid (Q1) of formula X₃—Y—COOHin the presence of a dehydrating agent such as dicyclohexylcarbodiimide(DCC) or N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(EDAC) and a catalytic amount of N,N-dimethylamino pyridine. Thereaction is carried out in an inert organic solvent such asN,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, apolyhalogenated aliphatic hydrocarbon at a temperature from 0° C. and50° C. The reaction is completed within a time range from 30 minutes to36 hours.

The compounds of formula (Q1), where X₃ is an halogen atom arecommercially available or can be obtained from the correspondingcommercially available hydroxy acid by well known reactions, for exampleby reaction with thionyl or oxalyl chloride, halides of P^(III) or P^(V)in solvents inert such as toluene, chloroform, DMF, etc.

The compounds (A) wherein R₁, R₂ are as above defined are commerciallyavailable.

The compounds of formula (E) can also be obtained as described below.The compounds of formula A are converted to the compounds (E) byreaction with a nitrooxy derivative of formula Cl(O)C—Y—ONO₂ containingan activated acylating group.

The nitrooxycompounds can be obtained from the corresponding alcohols offormula Cl(O)C—Y—OH by reaction with nitric acid and acetic anhydride ina temperature range from −50° C. to 0° C. or from the correspondinghalogen derivatives of formula Cl(O)C—Y-Hal by reaction with silvernitrate in the presence of an inert solvent such as acetonitrile,tetrahydrofurane. A silver nitrate molar excess is preferably used andthe reaction is carried out, in the dark, a temperature from the boilingtemperature and room temperature. The reaction is completed within atime range from 30 minutes to 3 days.

EXAMPLES

The following non-limiting examples further describe and enable one ofordinary skilled in the art to make and use the present invention.

Example 1 4-(Nitrooxymethyl)benzoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoateof formula (8)

1a. 4-(Chloromethyl)benzoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate

To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml)4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) andN,N-dimethylaminopyridine (catalytic amount) were added. The reactionwas stirred at room temperature for 24 hours. The solution was treatedwith water and the organic layer was dried over sodium sulphate. Thesolvent was evaporated and the residue was purified by flashchromatography eluting with n-hexane/ethyl acetate 6/4 (Rf=0.2). Thetitle product 0.27 g was obtained as a white powder.

1b. 4-(Nitrooxymethyl)benzoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate

A solution of the product of Example 1a (0.27 g, 0.48 mmol) and silvernitrate (0.16 g, 0.96 mmol) in acetonitrile (30 ml) was stirred at 60°C., in the dark, for 36 hours. The precipitated (silver salts) wasfiltered off and the solvent was evaporated under vacuum. The residuewas treated with chloroform and water. The organic layer was dried oversodium sulphate. The solvent was evaporated and the residue was purifiedby flash chromatography eluting with ethyl acetate/n-hexane 6/4. Thetitle product 0.03 g was obtained as a white powder.

¹H-NMR (DMSO) δ (ppm): 11.31 (1H,s); 8.15 (2H,m); 7.8-7.5 (2H,m); 7.43(1H,d); 7.30 (2H,m); 7.15-6.85 (7H,m); 6.77 (1Hd); 6.03 (1H,m); 5.65(2H,s); 4.55 (2H,m); 4.33 (2H,m); 4.0-3.7 (5H,m); 3.51 (2H,m).

Example 2 4-(Nitrooxymethyl)benzoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanoateof formula (11)

2a. 4-(Chloromethyl)benzoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-chloromethyl)benzoyl]amino]-2-propanoate

To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml)4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) andN,N-dimethylaminopyridine (catalytic amount) were added. The reactionwas stirred for 24 hours at room temperature. The solution was treatedwith water and the organic layer was dried over sodium sulfate andfiltered. The solvent was evaporated and the residue was purified byflash chromatography eluting with n-hexane/ethyl acetate 1/1 (Rf=0.42).The title product (0.06 g) was obtained as a white powder.

2b. 4-(Nitrooxymethyl)benzoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanoate

A solution of the product of example 2a (0.06 g, 0.08 mmol) and silvernitrate (0.06 g, 0.32 mmol) in acetonitrile (20 ml) was stirred at 60°C., in the dark, for 36 hours. The precipitated (silver salts) wasremoved by filtration. The filtrate was concentrated and the residue wastreated with chloroform and water. The combined organic layer extractswere dried over sodium sulfate and filtered. The solvent was evaporatedand the residue was purified by flash chromatography eluting withn-hexane/ethyl acetate 6/4. The title product 0.015 g was obtained as apowder.

¹H-NMR (DMSO) δ (ppm): 1.24 (1H,s); 8.1 (3H,m); 7.7-7.2 (8H,m); 7.2-6.7(8H,m); 6.05 (1H,m); 5.6-5.8 (4H,d); 4.55 (1H,m); 4.30 (2H,m); 4.15(3H,m); 3.71 (5H,s).

Example 31-(9H-carbazolyloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanolof formula (15)

3a.1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-chloromethyl)benzoyl]amino]-2-propanol

To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml)4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) andN,N-dimethylaminopyridine (catalytic amount) were added. The reactionwas stirred for 24 hours at room temperature. The solution was treatedwith water and the organic layer was dried over sodium sulfate andfiltered. The solvent was evaporated and the residue was purified byflash chromatography eluting with n-hexane/ethyl acetate 6/4 (Rf=0.42).The title product 1.05 g was obtained as a white powder.

3b.1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanol

A solution of the product of example 3a (1.0 g, 1.78 mmol) and silvernitrate (0.6 g, 3.6 mmol) in acetonitrile (100 ml) was stirred at 65°C., in the dark, for 32 hours. The precipitated (silver salts) wasremoved by filtration. The filtrate was concentrated and the residue wastreated with methylene chloride and water. The combined organic layerextracts were dried over sodium sulphate. The solvent was evaporated andthe residue was purified by flash chromatography eluting withn-hexane/ethyl acetate 1/1. The title product 0.4 g was obtained asyellow powder.

¹H-NMR (DMSO) δ (ppm): 11.24 (1H,s); 8.40-6.50 (15H,m); 5.61 (2H,m);5.51 (1H,m); 5.36 (1H,m); 4.40-3.90 (4H,m); 3.74-3.71 (7H,m).

Example 41-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(3-nitrooxypropanoyl)amino]-2-propanolof formula (112)

The compound was synthesized under the analogous procedure described inexample 3 starting from carvedilol and 3-bromopropanoic acid.

¹H-NMR (DMSO) δ (ppm): 11.24 (1H, s); 8.25 (1H, dd); 7.46 (1H, dd); 7.29(2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1H, dd); 5.50 (1H, d); 4.80(2H, m); 4.35 (1H, m); 4.20-3.6 (9H, m); 3.6-2.8 (4H, m).

Example 51-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(6-nitrooxyhexanoyl)amino]-2-propanolof formula (113)

The compound was synthesized under the analogous procedure described inexample 3 starting from carvedilol and 6-bromohexanoic acid.

¹H-NMR (DMSO) δ (ppm): 11.24 (1H, s); 8.25 (1H, dd); 7.46 (1H, dd); 7.29(2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1H, dd); 5.40 (1H, d);4.50-3.50 (13H, m); 2.6-2.3 (2H, m); 1.70-0.50 (6H, m).

Example 6 6-(nitrooxy)hexanoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-[(6-nitrooxyhexanoyl]amino]-2-propanolof formula (111)

The compound was synthesized under the analogous procedure described inexample 2 starting from carvedilol and 6-bromohexanoic acid.

¹H-NMR (DMSO) δ (ppm): 11.24 (1H, s); 8.15 (1H, dd); 7.46 (1H, dd); 7.29(2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1H, dd); 5.65 (1H, m);4.6-4.20 (6H, m); 4.2-3.5 (9H, m); 2.50 (2H, m); 2.29 (2H, m); 1.70-0.60(12H, m).

Example 7 6-(nitrooxy)hexanoic acid1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanolhydrochloride of formula (110)

The compound was synthesized under the analogous procedure described inexample 1 starting from carvedilol and 6-bromohexanoic acid.

¹H-NMR (DMSO) δ (ppm): 11.30 (1H, s); 8.15 (1H, dd); 7.44 (1H, dd); 7.32(2H, m); 7.10-6.90 (6H, m); 6.70 (1H, dd); 5.65 (1H, m); 4.50-4.20 (7H,m); 3.90-3.40 (7H, m); 2.40 (2H, m); 1.60-1.10 (6H, m).

Example 8 Measurements of cGMP in Rat PC12 Cell Line

cGMP contributes to the function and interaction of several vascularcell types and its dysfunction is involved in major cardiovasculardiseases such as hypertension, diabetic complications, atherosclerosis,and tissue infarction. Therefore the extent of cGMP formation elicitedby the compounds of the inventions was evaluated in the ratpheochromocytoma (PC12) cell line.

Tested Compounds

-   1) Carvedilol (parent drug)-   2)    1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanol    (compound of example 3);-   3) 4-(Nitrooxymethyl)benzoic acid    1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate    (compound of example 1);-   4)    1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(3-nitrooxypropanoyl)amino]-2-propanol    (compound of example 4);-   5)    1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(6-nitrooxyhexanoyl)amino]-2-propanol    (compound of example 5).    Method

Cells were maintained at 37° C. in DMEM medium enriched with 10% horseserum and 5% foetal bovine serum under 5% CO₂ atmosphere. At the time ofexperiments the cells were washed once with Hank's Balanced SaltSolution (HBSS) supplemented with 0.05% ascorbic acid and preincubatedin the same buffer for 10 min in a floating water bath. After thepreincubation step, cells were exposed for additional 45 min to eithercontrol conditions or increasing concentrations of test compoundsranging from 0.1 to 25 μM, in the presence of the phosphodiesteraseinhibitor, IBMX (100 μM) and the NO-independent activator of solubleguanylyl cyclase, YC-1 (20 μM). The reaction was terminated by theremoval of the incubating buffer and consecutive addition of 100 μl ofabsolute ethanol. The organic extracts were then evaporated to drynessand the residues dissolved in aqueous buffer for quantitativedetermination of intracellular cGMP levels using the cGMP enzymeimmunoassay kit.

The obtained results reported in Table 1 are expressed as EC₅₀ (μM) andefficacy Emax (% of vehicle). As shown in the table the nitroderivativesof carvedilol induced a consistent increase of intracellular cGMPformation in PC12 cell line. Conversely, this effect was not induced bythe parent compound.

TABLE 1 Effects of the nitroxyderivatives of carvedilol and thecarvedilol on cGMP accumulation in PC12 cells Compound EC₅₀ (μM) E_(max)(% of vehicle) Carvedilol Not effective Not effective Compound ofexample 3 1.8 565 Compound of example 1 2.3 480 Compound of example 41.7 395 Compound of example 5 0.6 322

1. A compound of general formula A-(Y—ONO₂)_(s) (I) and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, wherein s is an integer equal to 1; A is selected from the following β-adrenergic blockers residues of formula (II):

wherein R₁ is

R₂ is

Z is —C(O)—; Z₁ is H; Y is a bivalent radical selected from the group consisting of: a) straight or branched C₁-C₂₀ alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO₂ or T, wherein T is —OC(O)(C₁-C₁₀alkyl)-ONO₂, —O(C₁-C₁₀alkyl)-ONO₂; b)

wherein: n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1, R³ and R⁴ are independently selected from H or CH₃, Y¹ is —CH₂— or —(CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20; X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH; and c)

wherein X₂ is O or S, n10a, n10 and n12 are integer independently selected from 0 to 20, n11 is an integer from 0 to 6; R¹¹ is H, CH₃ or nitrooxy group; R^(11a) is CH₃ or nitrooxy group; and wherein (Y—ONO₂)_(s) bonds with Z of formula (II).
 2. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein Y is a straight or branched C₁-C₁₀ alkylene.
 3. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein Y is

wherein n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R³ and R⁴ are independently selected from H or CH₃; Y¹ is —CH₂— or —CH₂)_(na)—CH═CH— wherein na is an integer from 0 to 20; X₁ is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH.
 4. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 wherein n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10, Y¹ is CH₂.
 5. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 wherein n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer from 1 to 10, Y¹ is —(CH₂)_(na)—CH═CH— wherein na is 0, X₁ is —WC(O)— wherein W is oxygen and X₁ is bound to the phenyl ring through the [C]₄, R⁴ is CH₃ and the group (OR⁴) is bound to the phenyl ring through the [C]₃.
 6. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein Y is

wherein X₂ is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R¹¹ is H, CH₃ or a nitrooxy group; R^(11a) is CH₃ or a nitrooxy group.
 7. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 6 wherein Y is

wherein X₂ is O or S, n10a is an integer from 0 to 10 n11 are 0, n12 is an integer from 1 to 10, R¹¹ is H or a nitrooxy group; wherein the —ONO₂ group is bound to the —(CH₂)_(n12)— group.
 8. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein Y is a straight or branched C₁-C₂₀ alkylene being optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, —ONO₂ or T, wherein T is —OC(O)(C₁-C₁₀alkyl)-ONO₂, —O(C₁-C₁₀alkyl)-ONO₂.
 9. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 8 wherein Y is a straight or branched C₃-C₆ alkylene.
 10. Compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any one of claims 1, 8 or 9 wherein the compounds are:


11. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to claim 1, that is 4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate.
 12. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to any one of claim 1, 8 or 9, that is 6-(nitrooxy)hexanoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol hydrochloride.
 13. A medicament comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim
 1. 14. A method for the treatment or prophylaxis of hypertension, cardiovascular and vascular diseases using a drug comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim
 1. 15. A method for the treatment of glaucoma and elevated intraocular pressure using a drug comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim
 1. 16. A pharmaceutical composition comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1 and at least one pharmaceutically acceptable carrier. 